In multicellular organisms, homeostasis is maintained by balancing the rate of cell proliferation against the rate of cell death. Cell proliferation is influenced by numerous growth factors and the expression of proto-oncogenes, which typically encourage progression through the cell cycle. In contrast, numerous events, including the expression of tumor suppressor genes, can lead to an arrest of cellular proliferation.
In differentiated cells, a particular form of cell death called apoptosis is carried out when an internal suicide program is activated. This program can be initiated by a variety of external signals as well as signals that are generated within the cell in response to, for example, genetic damage. For many years, the magnitude of apoptotic cell death was not appreciated because the dying cells are quickly eliminated by phagocytes, without an inflammatory response.
The mechanisms that mediate apoptosis have been intensively studied. These mechanisms involve the activation of endogenous proteases, loss of mitochondrial function, and structural changes such as disruption of the cytoskeleton, cell shrinkage, membrane blebbing, and nuclear condensation due to degradation of DNA. The various signals that trigger apoptosis are thought to bring about these events by converging on a common cell death pathway that is regulated by the expression of genes that are highly conserved from worms, such as C. elegans, to humans. In fact, invertebrate model systems have been invaluable tools in identifying and characterizing the genes that control apoptosis. Through the study of invertebrates and more evolved animals, numerous genes that are associated with cell death have been identified, but the way in which their products interact to execute the apoptotic program is poorly understood.
Recently, several polypeptides were discovered which form a complex that transmits an apoptotic signal when the Fas/APO-1 receptor is bound (Boldin et al., Cell 85:803, 1996; Muzio et al., Cell 85:817, 1996). This receptor, also known as CD95, is present on the surface of a wide variety of cells (Boldin et al., supra; Muzio et al., supra). The Fas/APO-1 receptor and the TNF receptor (described below) are classified as members of the TNF/nerve growth factor receptor family and both share a region of homology designated the "death domain" (Boldin et al., supra; Muzio et al., supra). The death domain of the Fas/APO-1 receptor interacts with FADD (Fas-associating protein with death domain, also known as MORT1) and RIP (receptor interacting protein), forming a complex that, when joined by Caspas-8, constitutes the Fas/APO-1 death-inducing signalling complex (Boldin et al., supra; Muzio et al., supra). The interaction between Fas/APO-1 and FADD is mediated by their respective C-terminal death domains (Chinnaiyan et al., Cell 81:505-512, 1995). Caspase-8 contains two N-terminal stretches of approximately 60 amino acids that are homologous to the DED of FADD (Muzio et al., supra). The remainder of Caspase-8 is highly homologous to the ICE/CED-3 family of cysteine proteases, which induce cell death if overexpressed. A number of forms of Caspase-8 have been described (Boldin et al., supra).
Caspase-8 may also be an important part of a second complex which is involved in cell death. This complex forms in association with the intracellular portion of the tumor necrosis factor (TNF) receptor (TNFR-1 or p55-R), and includes Caspase-8, TRADD (TNFR-1-associated death domain protein), and FADD/MORT1 (Boldin et al., supra; Muzio et al., supra).